Hemolytic Anemia

Updated: Mar 06, 2019

Author: Paul Schick, MD; Chief Editor: Emmanuel C Besa, MD

Overview

Background

Hemolysis is the premature destruction of erythrocytes. A hemolytic anemia will develop if bone marrow activity cannot compensate for the erythrocyte loss. The severity of the anemia depends on whether the onset of hemolysis is gradual or abrupt and on the extent of erythrocyte destruction. Mild hemolysis can be asymptomatic while the anemia in severe hemolysis can be life threatening and cause angina and cardiopulmonary decompensation.

Hemolytic anemia has multiple causes, and the clinical presentation can differ depending on the etiology. An array of laboratory tests are available for detecting hemolysis, and specialized tests may be indicated to diagnose the cause for hemolysis (see Workup). There are differences in the management of various types of hemolytic anemias (see Treatment).

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Pathophysiology

Hemolysis can be due to hereditary and acquired disorders.[1, 2] The etiology of premature erythrocyte destruction is diverse and can be due to conditions such as intrinsic membrane defects, abnormal hemoglobins, erythrocyte enzymatic defects, immune destruction of erythrocytes, mechanical injury, and hypersplenism.

Hemolysis may be an extravascular or an intravascular phenomenon. Autoimmune hemolytic anemia and hereditary spherocytosis are examples of extravascular hemolysis because the red blood cells are destroyed in the spleen and other reticuloendothelial tissues.[3] Intravascular hemolysis occurs in hemolytic anemia due to the following:

Prosthetic cardiac valves

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Thrombotic thrombocytopenic purpura

Disseminated intravascular coagulation

Transfusion of ABO incompatible blood

Paroxysmal nocturnal hemoglobinuria (PNH)

Hemolysis may also be intramedullary, when fragile red blood cell (RBC) precursors are destroyed in the bone marrow prior to release into the circulation. Intramedullary hemolysis occurs in pernicious anemia and thalassemia major.

Hemolysis is associated with a release of RBC lactate dehydrogenase (LDH). Hemoglobin released from damaged RBCs leads to an increase in indirect bilirubin and urobilinogen levels.

A patient with mild hemolysis may have normal hemoglobin levels if increased RBC production matches the rate of RBC destruction. However, patients with mild hemolysis may develop marked anemia if their bone marrow erythrocyte production is transiently shut off by viral (parvovirus B-19) or other infections. This scenario would be an aplastic crisis since the bone marrow can no longer compensate for ongoing hemolysis.

Skull and skeletal deformities can occur in childhood due to a marked increase in hematopoiesis and resultant bone marrow expansion in disorders such as thalassemia.

Etiology

A wide range of causes of hemolytic anemia have been documented.[4, 5, 6, 7, 8, 9, 10, 11, 12, 1, 13] Only the more commonly encountered hemolytic disorders are discussed in this article.

Autoimmune hemolytic anemia (AIHA) can be due to warm or cold autoantibody types and, rarely, mixed types.[13, 20, 21, 22] Most warm autoantibodies belong to the immunoglobulin IgG class. These antibodies can be detected by a direct Coombs test, which also is known as a direct antiglobulin test (DAT). AIHA may occur after allogeneic hematopoietic stem cell transplantation. The 3-year cumulative incidence in this population has been reported at 4.44%.[23]

AIHA is rare in children and has a range of causes. Autoimmune hemolysis can be primary or secondary to conditions such as infections (viral, bacterial, and atypical), systemic lupus erythematosus (SLE), autoimmune hepatitis (AIH), and H1N1 influenza. H1N1 influenza–associated AIHA in children may respond to treatment with oseltamivir and intravenous immunoglobulin.[6]

Fetal splenomegaly and associated hepatomegaly could be due to hemolysis, but infections are the most likely cause. Congestive heart failure and metabolic disorders should be considered. Rarely, leukemia, lymphoma, and histiocytosis are associated with splenomegaly.[24]

Microangiopathic hemolytic anemia, which results in the production of fragmented erythrocytes (schistocytes), may be caused by any of the following[25, 26] :

Defective prosthetic cardiac valves

Disseminated intravascular coagulation (DIC)

Hemolytic uremic syndrome (HUS)

Thrombotic thrombocytopenic purpura (TTP)

In paroxysmal nocturnal hemoglobinuria, hemolysis is due to intravascular complement-mediated destruction of erythrocytes.

Epidemiology

Hemolytic anemia represents approximately 5% of all anemias. Acute AIHA is relatively rare, with an incidence of one to three cases per 100,000 population per year.[27]

Hemolytic anemias are not specific to any race. However, sickle cell disorders are found primarily in Africans, African Americans, some Arabic peoples, and Aborigines in southern India.

Several variants of G6PD deficiency exist. The A(-) variant is found in West Africans and African Americans. Approximately 10% of African Americans carry at least 1 copy of the gene for this variant. The Mediterranean variant occurs in individuals of Mediterranean descent and in some Asians.

Most cases of hemolytic anemia are not sex specific. However, AIHA is slightly more likely to occur in females than in males. G6PD deficiency is an X-linked recessive disorder. Therefore, males are usually affected, and females are carriers.

Although hemolytic anemia can occur in persons of any age, hereditary disorders are usually evident early in life. AIHA is more likely to occur in middle-aged and older individuals.

Prognosis

The prognosis for patients with hemolytic anemia depends on the underlying cause.

Overall, mortality rates are low in hemolytic anemias. However, the risk is greater in older patients and patients with cardiovascular impairment.

Morbidity depends on the etiology of the hemolysis and the underlying disorder, such as sickle cell anemia or malaria.

Patient Education

Patients should be able to identify symptoms and signs of the recurrence of hemolysis. They should seek prompt medical attention if symptoms reoccur.

Patients with G6PD deficiency should know which medications to avoid.

For patient education information, see the Blood and Lymphatic System Center, as well as Anemia.

Presentation

History

Signs and symptoms of hemolytic anemia are diverse and are due to anemia, the extent of compensation, previous treatment, and the underlying disorder. Patients with minimal or long-standing hemolytic anemia may be asymptomatic, and hemolysis is often found incidentally during routine laboratory testing. Clinical manifestations may include the following:

In intravascular hemolysis, iron deficiency due to chronic hemoglobinuria can exacerbate anemia and weakness.

Tachycardia, dyspnea, angina, and weakness occur in patients with severe anemia, as cardiac function is sensitive to anoxia.

Persistent hemolysis may result in the development of bilirubin gallstones; these patients may present with abdominal pain.

Bronze skin color and diabetes occur in hematosiderosis; iron overload may occur in patients who have received multiple transfusions or those who have been administered iron therapy erroneously.

Leg ulcers may develop in patients with sickle cell anemia and other hemolytic disorders, as a result of decreased red blood cell (RBC) deformability and endothelial changes.

Venous thromboembolism occurs in 15% to 33% of adults with warm autoimmune hemolytic anemia, especially in the first few weeks after onset.[28] Children with hereditary spherocytosis (HS) are also at increased risk for thrombosis. Hypercoagulability is especially marked in children with HS who are experiencing a hemolytic crisis.[29]

Patients may report recent use of medications that can cause immune hemolysis. These include penicillin, quinine, quinidine, and L-dopa. Dimethyl fumarate has recently been shown to cause a hemolytic anemia.[30]

In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemolysis can be triggered by oxidant drugs and stress from infections. Fava beans can induce hemolysis in susceptible individuals with the Mediterranean variant of G6PD deficiency.

Physical Examination

The physical examination in an individual with hemolytic anemia can reveal signs of anemia, complications of hemolysis, and evidence of an underlying disease. General pallor and pale conjunctivae and fingernails indicate anemia but are not specific for hemolytic anemias. Tachycardia, tachypnea, and hypotension due to anoxia and decreased vascular volume can occur in severe anemias but are not specific for hemolytic anemias.

Jaundice may occur because of a modest increase in indirect bilirubin in hemolysis. The rise is not specific for hemolytic disorders and may occur in liver disease and biliary obstruction. Bilirubin levels are rarely greater than 3 mg/dL in hemolysis, unless complicated by hepatic disease or cholelithiasis.

Splenomegaly occurs in hereditary spherocytosis and other hemolytic anemias, but it is not present in all hemolytic disorders. For example, splenomegaly usually is not present in G6PD deficiency. The presence of splenomegaly could suggest an underlying disorder such as chronic lymphocytic leukemia (CLL), some lymphomas, or systemic lupus erythematosus (SLE). Butterfly malar rash and arthritis also suggest SLE. Lymphadenopathy along with splenomegaly is consistent with CLL.

Splenomegaly sometimes is not evident on physical examination, and ultrasonic imaging or CT scanning may be necessary to define spleen size. When evaluating spleen size, it is important to avoid unnecessary pressure in order to avoid splenic rupture.

Tachycardia and dyspnea may be evident when the onset of hemolysis is abrupt and the anemia is severe. Angina and heart failure symptoms can occur in patients with underlying cardiovascular disease.

In patients with chronic hemolytic anemia, increased folate consumption may lead to folate deficiency. Clinical manifestations may include patchy hyperpigmentation, sore tongue, and gastrointestinal symptoms.

DDx

Diagnostic Considerations

Other causes for fatigue, tachycardia, and dyspnea should be considered. Other causes for anemia should be ruled out. A transfusion requirement in the absence of blood loss or bone marrow aplasia would suggest hemolysis.

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Differential Diagnoses

Workup

Approach Considerations

Standard blood studies for the workup of suspected hemolytic anemia include the following:

Complete blood cell count

Peripheral blood smear

Serum lactate dehydrogenase (LDH)

Serum haptoglobin

Indirect bilirubin

Hemolysis of collected blood is more likely to occur in standard large vacuum tubes than in small tubes. Thus, it might better to collect blood for these tests in small vacuum tubes, since hemolysis of collected blood can skew the results of these tests.[31]

Changes in the LDH and serum haptoglobin levels are the most sensitive general tests because the indirect bilirubin is not always increased.

Other laboratory studies may be directed by history, physical examination, peripheral smear, and other laboratory findings. Ultrasonography is used to estimate the spleen size, since the physical examination occasionally does not detect significant splenomegaly. Chest radiography, electrocardiography (ECG), and other studies are used to evaluate cardiopulmonary status.

See the algorithm below.

Hemolytic anemia algorithm.

Complete Blood Cell Count

This test can detect an anemia, pancytopenia, and infections. Along with the differential count, a CBC count can help diagnose hematologic malignancies and other hematological disorders. The platelet count usually is normal in most hemolytic anemias.

Red blood cell indices

These studies are performed when a CBC count is requested. A low mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) are consistent with a microcytic hypochromic anemia due to iron deficiency that may occur in chronic intravascular hemolysis.

A high MCV is consistent with a macrocytic anemia. Folate consumed during chronic hemolysis may lead to megaloblastosis and a high MCV. However, the MCV also may be elevated in patients with high reticulocyte counts since these cells are larger than mature RBCs. A high MCH and mean corpuscular hemoglobin concentration (MCHC) would suggest spherocytosis.

Red blood cell distribution width study

The red blood cell distribution width (RDW) study is usually performed when a CBC count is requested. An increased RDW is a measure of anisocytosis that can occur in hemolytic anemias.

Reticulocyte count

An increased reticulocyte count represents increased RBC production and is a criterion for hemolysis but is not specific for hemolysis. In addition to hemolysis, increased reticulocytes may be a response to blood loss or the treatment of iron, vitamin B-12, or folate deficiencies. The reticulocyte count may be normal or low in patients with bone marrow suppression despite ongoing severe hemolysis (aplastic crisis).

Peripheral Blood Smear

Peripheral smear findings can help in the diagnosis of a concomitant underlying hematologic malignancy associated with hemolysis. For example, smears in CLL are characterized by an abundance of small lymphocytes and smudge cells (ruptured CLL cells).

The following are examples of the value of evaluating peripheral blood smears.

Lactate Dehydrogenase Study

LDH elevation is sensitive for hemolysis, but is not specific since LDH is ubiquitous and can be released from neoplastic cells, the liver, or from other damaged organs.

Although an increase in LDH isozymes 1 and 2 is more specific for red blood cell destruction, these enzymes are also increased in patients with myocardial infarction.

Serum Haptoglobin

A low serum haptoglobin level is a criterion for moderate-to-severe hemolysis.

A decrease in serum haptoglobin is more likely in intravascular hemolysis than in extravascular hemolysis.

However, it is an acute phase reactant. Therefore, haptoglobin levels can be normal or elevated despite significant hemolysis in patients with infections and in other reactive states.

Indirect Bilirubin

Unconjugated bilirubin is a criterion for hemolysis, but it is not specific because an elevated indirect bilirubin level also occurs in Gilbert disease.

With hemolysis, the level of indirect bilirubin usually is less than 3 mg/dL. Higher levels of indirect bilirubin indicate compromised hepatic function or cholelithiasis.

Other Laboratory Studies

The following specific studies may be indicated:

Direct antiglobulin test (DAT)

Urine free hemoglobin test

Urine hemosiderin test

Red blood cell survival test

Cold agglutinin titer

Glucose-6-phosphate dehydrogenase (G6PD) screen

Sickle cell screen

The DAT result is usually positive in autoimmune hemolytic anemia (AIHA), but it may occasionally be negative in this disorder. DAT-negative AIHAs have been reviewed.[33] From 5-10% of all AIHAs are DAT negative. The polybrene test can detect DAT-negative AIHA.[33] In addition, the immunoradiometric assay (IRMA) for red blood cell–bound IgG can be used to diagnose AIHA in patients whose autoantibody levels are too low to be detected by conventional DAT.[34] DAT-negative AIHA has a better prognosis than DAT-positive AIHA.[35]

A promising method for diagnosing AIHA has been developed. The test measures the binding of red blood cells that have autoimmune IgG on their surface to films containing a monoclonal antibody against human immunoglobulin. The test could be used in place of the direct Coombs test, which is prone to false positives.[36]

MicroRNA analysis has been found to be helpful in the diagnosis of AIHA in patients with chronic lymphocytic leukemia.[37]

In addition to hemoglobinuria, either myoglobinuria or porphyria may result in dark urine. To rule out these possibilities, the urine should be tested for free hemoglobin. Hemoglobinuria occurs when the amount of free hemoglobin released during hemolysis exceeds available haptoglobin.

Urine hemosiderin may suggest severe or intravascular hemolysis. Hemosiderin is detected in iron-stained urinary sediment in sloughed renal epithelial cells. The source of urinary hemosiderin is hemoglobinuria that occurs in severe and intravascular hemolysis. When urinary hemoglobin is reabsorbed by renal tubular cells, it is processed to hemosiderin. Therefore, urinary hemosiderin reflects hemoglobinuria and suggests severe or intravascular hemolysis.

Red blood cell survival (chromium-51 [51 Cr] survival) is rarely used, but it can definitively demonstrate shortened red blood cell survival (hemolysis). If available, this test can be helpful when the clinical history and laboratory studies cannot establish a diagnosis of hemolysis.

The cold agglutinin titer will be elevated in cold agglutinin disease, with the specific IgM antibody varying according to the underlying disorder. For example, a high titer of anti-I antibody (ie, antibody directed against the I antigen found on normal adult RBCs) occurs in mycoplasmal infections. High titers of anti-i antibody (antibody directed against the i antigen found on fetal cord blood RBCs) have been reported in infectious mononucleosis. An anti-P cold agglutinin may be seen in paroxysmal cold hemoglobinuria.

A G6PD screening can usually detect deficiency of this enzyme, but results can be normal if the reticulocyte count is elevated (reticulocytes contain a considerable amount of G6PD). A positive Heinz body preparation can suggest denatured hemoglobin and thus G6PD deficiency (see the image below).

Other tests may be indicated to diagnose hereditary spherocytosis, hematologic malignancy, and rarer types of hemolytic anemias.

Treatment

Approach Considerations

There are numerous types of hemolytic anemia, and treatment may differ depending on the type of hemolysis.[4, 5, 6, 38, 39, 40] Only the general care of hemolytic anemias and the management of the most commonly encountered hemolytic anemias are discussed. The diagnosis and treatment of cold agglutinin hemolytic anemia has been reviewed.[41]

Folic acid, corticosteroids, rituximab, and IVIG

Increasing evidence supports the use of rituximab in AIHA, particularly warm antibody AIHA.[42, 42] Results of a phase III trial in 64 patients support its use as first-line therapy for warm AIHA, in combination with corticosteroids. Birgens et al reported that after 12 months, a satisfactory response was observed in 75% of the patients treated with rituximab and prednisolone, but in 36% of those given prednisolone alone (P = 0.003). After 36 months, about 70% of the patients who had received rituximab and prednisolone were still in remission, compared with about 45% of those in the prednisolone group.[39]

Intravenous immunoglobulin G (IVIG) has been used for patients with AIHA, but only a few patients have responded to this treatment, and the responses have been transient.

Transfusion Therapy

One should avoid transfusions unless absolutely necessary. However, transfusions may be essential for patients with angina or a severely compromised cardiopulmonary status. It is best to administer packed red blood cells slowly to avoid cardiac stress.

In autoimmune hemolytic anemia (AIHA), typing and cross-matching may be difficult. One should use the least incompatible blood if transfusions are indicated. The risk of destruction of transfused blood is high, but the degree of the hemolysis depends on the rate of infusion. Therefore, one should slowly transfuse half units of packed red blood cells to prevent rapid destruction of transfused blood.

Iron overload due to multiple transfusions for chronic anemia (eg, thalassemia or sickle cell disorder) can be treated with chelation therapy. A systematic review that compared the oral iron chelator deferasirox with the oral chelator deferiprone and the traditional parenteral agent deferoxamine found little clinical difference between the 3 chelation agents in terms of removing iron from the blood and liver.[43]

Erythropoietin Therapy

Erythropoietin (EPO) has been used to try to reduce transfusion requirements, with variable outcomes. Settings in which EPO therapy has reduced transfusion requirements include the following:

However, the ability of EPO to reduce transfusion requirement has been questioned in newborns with hereditary spherocytosis[50] and in post-diarrheal hemolytic uremic syndrome.[51]

There is a general impression that additional studies should be carried out to establish the role and indications for EPO in hemolytic disorders. EPO therapy costs more than transfusions. The potential for EPO-induced cardiovascular complications needs to be considered. EPO has pleiotropic effects and might inhibit macrophages in Salmonella infections.[52] EPO was reported to be helpful in treating cerebral malaria due to itspleiotropic effect and not its hematopoietic action.[53] Hence, EPO should be used judiciously.

Discontinuing Medications

Penicillin and other agents that can cause immune hemolysis should be discontinued in patients who develop hemolysis. The following is a partial list of medications that can cause immune hemolysis:

Penicillin

Cephalothin

Ampicillin

Methicillin

Quinine

Quinidine

One should discontinue oxidant medications such as sulfa drugs in patients with G-6-PD deficiency or those who have unstable hemoglobins. The following is a partial list of medications and chemicals that should be avoided in G6PD deficiency:

Acetanilide

Furazolidone

Isobutyl nitrite

Nalidixic acid

Naphthalene

Niridazole

Iron Therapy

Iron therapy is contraindicated in most cases of hemolytic anemia. The reason is that iron released from RBCs in most hemolytic anemias is reused and iron stores are not reduced.

However, iron therapy is indicated for patients with severe or intravascular hemolysis in which persistent hemoglobinuria has caused substantial iron loss. Before starting iron therapy, one should document iron deficiency by serum iron studies and, possibly, by assessing iron stores in bone marrow aspirates.

Splenectomy

Splenectomy may be the first choice of treatment in some types of hemolytic anemia, such as hereditary spherocytosis.[54] In other cases, such as in AIHA, splenectomy is recommended when other measures have failed. Splenectomy is usually not recommended in hemolytic disorders such as cold agglutinin hemolytic anemia in which hemolysis is intravascular.

Overwhelming postsplenectomy sepsis is a rare but a potentially fatal event, especially during the first 2 years after splenectomy. One should immunize against infections with encapsulated organisms, such as Haemophilus influenzae and Streptococcus pneumoniae, in advance of the procedure. Immunization can be performed post splenectomy.

Deterrence/Prevention of Hemolytic Anemia

The following is a partial list of medications and chemicals that individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency should avoid:

Acetanilid

Furazolidone

Isobutyl nitrite

Nalidixic acid

Naphthalene

Niridazole

Sulfa drugs

The G6PD Deficiency Association has a more comprehensive online list of medications that people with G6PD deficiency should avoid.

Patients should know to avoid medications that caused them to have immune hemolysis. The following is a partial list of medications that can cause immune hemolysis:

Penicillin

Cephalothin

Ampicillin

Methicillin

Quinine

Quinidine

Consultations

A hematology consultation would be helpful in selecting appropriate diagnostic approaches and laboratory tests and in planning and monitoring therapy.

Long-Term Monitoring

One should monitor the hemoglobin level, reticulocyte count, indirect bilirubin value, LDH level, and haptoglobin value in patients with hemolytic anemia to determine the response to therapy. Urine hemoglobin and hemosiderin should be monitored to evaluate recovery in patients with severe or intravascular hemolysis.

Other treatments are as follows:

Folic acid should be recommended for patients with ongoing hemolysis.

Administer oral iron to patients who have become iron deficient due to intravascular hemolysis.

One should taper corticosteroids. Occasionally, patients may have to continue low-dose steroids.

Avoid transfusions unless there is evidence of angina, cardiopulmonary decompensation, or other severe organ impairment.

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications in patients with hemolytic anemia. Treatment is specific to the type of hemolytic anemia. For example, corticosteroids are usually the first line of treatment in autoimmune hemolytic anemia (AIHA) but are seldom effective in pediatric cold agglutinin disease. Rituximab has been used and can be effective in steroid-resistant AIHA.[42, 55]

Vitamins

Class Summary

Vitamins are essential for normal DNA synthesis and the formation of a number of coenzymes in many metabolic systems.

Folic acid (Folacin-800)

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the immune response of the body to diverse stimuli.

Glucocorticoids, such as prednisone, are usually the first line of treatment in autoimmune hemolytic anemia (AIHA). Consult a hematologist to individualize therapy and determine whether other forms of therapy are indicated in the treatment of AIHA. Taper glucocorticoids very gradually to avoid a relapse of hemolysis.

Prednisone

Prednisone inhibits phagocytosis of antibody-covered red blood cells. This agent is indicated in some hemolytic disorders such as AIHA.

Iron Salts

Class Summary

Iron therapy is contraindicated in most hemolytic anemias. However, iron therapy is indicated for patients with severe intravascular hemolysis in which persistent hemoglobinuria has caused substantial iron loss.

Ferrous sulfate (Feosol, Fer-In-Sol, MyKidz iron 10)

Ferrous sulfate is the most common and inexpensive form of iron used. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain a smaller dose of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.

Ronald A Sacher, MBBCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences